Synthesis and Characterization of Tetraphenylethene AIEgen-Based Push-Pull Chromophores for Photothermal Applications: Could the Cycloaddition-Retroelectrocyclization Click Reaction Make Any Molecule Photothermally Active?

Three new tetraphenylethene (TPE) push-pull chromophores exhibiting strong intramolecular charge transfer (ICT) are described. They were obtained via [2 + 2] cycloaddition-retroelectrocyclization (CA-RE) click reactions on an electron-rich alkyne-tetrafunctionalized TPE (TPE-alkyne) using both 1,1,2,2-tetracyanoethene (TCNE), 7,7,8,8-tetracyanoquinodimethane (TCNQ) and 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane (F4-TCNQ) as electron-deficient alkenes. Only the starting TPE-alkyne displayed significant AIE behavior, whereas for TPE-TCNE, a faint effect was observed, and for TPE-TCNQ and TPE-F4-TCNQ, no fluorescence was observed in any conditions. The main ICT bands that dominate the UV-Visible absorption spectra underwent a pronounced red-shift beyond the near-infrared (NIR) region for TPE-F4-TCNQ. Based on TD-DFT calculations, it was shown that the ICT character shown by the compounds exclusively originated from the clicked moieties independently of the nature of the central molecular platform. Photothermal (PT) studies conducted on both TPE-TCNQ and TPE-F4-TCNQ in the solid state revealed excellent properties, especially for TPE-F4-TCNQ. These results indicated that CA-RE reaction of TCNQ or F4-TCNQ with donor-substituted are promising candidates for PT applications.

Fluorescent Dynamic Covalent Polymers for DNA Complexation and Templated Assembly.

Dynamic covalent polymers (DCPs) offer opportunities as adaptive materials of particular interest for targeting, sensing and delivery of biological molecules. In this view, combining cationic units and fluorescent units along DCP chains is attractive for achieving optical probes for the recognition and delivery of nucleic acids. Here, we report on the design of acylhydrazone-based DCPs combining cationic arginine units with π-conjugated fluorescent moieties based on thiophene-ethynyl-fluorene cores. Two types of fluorescent building blocks bearing neutral or cationic side groups on the fluorene moiety are considered in order to assess the role of the number of cationic units on complexation with DNA. The (chir)optical properties of the building blocks, the DCPs, and their complexes with several types of DNA are explored, providing details on the formation of supramolecular complexes and on their stability in aqueous solutions. The DNA-templated formation of DCPs is demonstrated, which provides new perspectives on the assembly of fluorescent DCP based on the nucleic acid structure.

Coupling radiative, conductive and convective heat-transfers in a single Monte Carlo algorithm: A general theoretical framework for linear situations.

It was recently shown that radiation, conduction and convection can be combined within a single Monte Carlo algorithm and that such an algorithm immediately benefits from state-of-the-art computer-graphics advances when dealing with complex geometries. The theoretical foundations that make this coupling possible are fully exposed for the first time, supporting the intuitive pictures of continuous thermal paths that run through the different physics at work. First, the theoretical frameworks of propagators and Green's functions are used to demonstrate that a coupled model involving different physical phenomena can be probabilized. Second, they are extended and made operational using the Feynman-Kac theory and stochastic processes. Finally, the theoretical framework is supported by a new proposal for an approximation of coupled Brownian trajectories compatible with the algorithmic design required by ray-tracing acceleration techniques in highly refined geometry.

Hypnosis associated with 3D immersive virtual reality technology during bronchoscopy under local anesthesia.

Background: Patients undergoing flexible bronchoscopy under local anesthesia usually experience anxiety before and during the procedure. Different non-pharmacological techniques, including music and hypnosis, are used to distract patients' attention, and to reduce anxiety. The new technique "virtual reality hypnosis (VRH)", defined as a hypnotic induction suggestion delivered by personalized virtual reality software, can generate a simulation of a lifelike environment. No study has described the use of VRH during bronchoscopy. The objective is to investigate the anxiety reducing effect and the satisfaction of patients, physicians, and nurses using VRH during bronchoscopy. Methods: VRH was proposed to all patients who experienced anxiety before undergoing flexible bronchoscopy under local anesthesia. Local anesthesia was performed using 5% lidocaine spray only. No sedation was used. After the procedure, patients, physicians and nurses filled a standardized satisfaction form. Results: Twenty consecutive patients who reported pre-procedure anxiety were included. The sex ratio was 16 women/4 men, the median age was 65 years. Eight patients (40%) had undergone a previous bronchoscopy under local anesthesia. The median duration of the procedure was 10 minutes, and all procedures were completed. The median level of anxiety of patients decreased from 9/10 before the procedure to 4/10 during the procedure. The median satisfaction rate regarding the use of VRH was 10/10. All patients agreed to use VRH again in case of a new bronchoscopy procedure. Conclusions: This preliminary report has shown that VRH was useful to reduce patients' anxiety during bronchoscopy under local anesthesia. VRH was easily implemented in the routine practice.

Aggregation-induced emission from silole-based lumophores embedded in organic-inorganic hybrid hosts.

Aggregation-induced emitters - or AIEgens - are often symbolised by their photoluminescence enhancement as a result of aggregation in a poor solvent. However, for some applications, it is preferable for the AIE response to be induced in the solid-state. Here, the ability of an organic-inorganic hybrid polymer host to induce the AIE response from embedded silole-based lumophores has been explored. We have focussed on understanding how the incorporation method controls the extent of lumophore aggregation and thus the associated photophysical properties. To achieve this, two sample concentration series have been prepared, based on either the parent AIEgen 1,1-dimethyl-2,3,4,5-tetraphenylsilole (DMTPS) or the silylated analogue (DMTPS-Sil), which were physically doped or covalently grafted, respectively, to dU(600) - a member of the ureasil family of poly(oxyalkylene)/siloxane hybrids. Steady-state and time-resolved photoluminescence measurements, coupled with confocal microscopy studies, revealed that covalent grafting leads to improved dispersibility of the AIEgen, reduced scattering losses, increased photoluminescence quantum yields (up to ca. 40%) and improved chemical stability. Moreover, the ureasil also functions as a photoactive host that undergoes excitation energy transfer to the embedded DMTPS-Sil with an efficiency of almost 70%. This study highlights the potential for designing complex photoluminescent hybrid polymers exhibiting an ehanced AIE response for solid-state optical applications.

Investigation of Coagulation Biomarkers to Assess Clinical Deterioration in SARS-CoV-2 Infection.

Since December 2019, a pandemic caused by a new coronavirus has spread to more than 170 countries around the world. Worsening infected patients requiring intensive care unit (ICU) admission associated with 30% of mortality. A part of worsening is induced by hemostasis deregulation. The aim of this study was to investigate the association of coagulation activation in COVID-19 progression. Thirty-five of the 99 patients got clinically worse. The final model of the logistic regression analysis revealed that O2 requirement (RR = 7.27 [1.50-19.31]), monocytes below 0.2G/L (RR = 2.88 [1.67-3.19]), fibrinogen levels (RR = 1.45 [1.17-1.82] per g/L increase), prothrombin fragments 1+2 higher than 290 pM (RR = 2.39 [1.20-3.30]), and thrombin peak (RR = 1.28 [1.03-1.59] per 50 nM increase) were associated with an increased risk of clinical worsening. A fibrinogen level threshold of 5.5 g/L, a thrombin peak measurement threshold of 99 pM, and O2 requirement associated with clinical outcome in more than 80% of our cohort. In conclusion, we identified fibrinogen and thrombin peak at admission as coagulation biomarkers associated with an increased risk of ICU admission or death. This finding allows initiating steroids and triage for worsening patients. Our results should therefore be considered as exploratory and deserve confirmation.

A simple endoscopic method with radial endobronchial ultrasonography for low-migration rate coil-tailed fiducial marker placement.

BACKGROUND: Fiducial markers (FMs) are useful for tracking small peripheral lung nodules (PLN) before stereotactic radiotherapy, but migration over the course of treatment may result in inaccurate dosing to the tumor. To minimize FM migration, coil-tailed FMs have been designed. Our objective was to assess both the feasibility of radial endobronchial ultrasonography (r-EBUS) placement and the migration rate of coil-tailed FMs. METHODS: In this retrospective study, we included patients who received r-EBUS guided placement of coil-tailed FMs for PLN <25 mm from June 2015 to May 2018. We introduced the FM into the nodule with the use of bronchial brush, without fluoroscopy. RESULTS: Thirty patients had r-EBUS guided placement of a coil-tailed FM before stereotactic radiation therapy. Nodule's median long- and short-axis diameters were 15 mm (8-25 mm) and 8 mm (5-20 mm), respectively; short diameter of 27 nodules (90%) was less than 15 mm. All nodules were reached and visualized with r-EBUS, with an ultrasound (US) signal showing a centered or tangential probe in 26 and 4 cases, respectively. No immediate complication was reported. Twenty-three patients had stereotactic radiation therapy within a median time of 29 days (14-126 days). No FM migration occurred between r-EBUS placement and radiotherapy. Pre-treatment planning and 3-month follow-up CT scans showed that all FMs stayed in direct contact with the lesions. CONCLUSIONS: r-EBUS is a safe procedure for the placement of nitinol coil FMs, which have a low migration rate.

A Cationic Tetraphenylethene as a Light-Up Supramolecular Probe for DNA G-Quadruplexes.

Guanine-quadruplexes (G4s) are targets for anticancer therapeutics. In this context, human telomeric DNA (HT-DNA) that can fold into G4s sequences are of particular interest, and their stabilization with small molecules through a visualizable process has become a challenge. As a new type of ligand for HT-G4, we designed a tetraimidazolium tetraphenylethene (TPE-Im) as a water-soluble light-up G4 probe. We study its G4-binding properties with HT-DNA by UV-Visible absorption, circular dichroism and fluorescence spectroscopies, which provide insights into the interactions between TPE-Im and G4-DNA. Remarkably, TPE-Im shows a strong fluorescence enhancement and large shifts upon binding to G4, which is valuable for detecting G4s. The association constants for the TPE-Im/G4 complex were evaluated in different solution conditions via isothermal titration calorimetry (ITC), and its binding modes were explored by molecular modeling showing a groove-binding mechanism. The stabilization of G4 by TPE-Im has been assessed by Fluorescence Resonance Energy Transfer (FRET) melting assays, which show a strong stabilization (ΔT 1/2 around +20°C), together with a specificity toward G4 with respect to double-stranded DNA.

Increased frequency of anti-Ma2 encephalitis associated with immune checkpoint inhibitors.

OBJECTIVE: To report the induction of anti-Ma2 antibody-associated paraneoplastic neurologic syndrome (Ma2-PNS) in 6 patients after treatment with immune checkpoint inhibitors (ICIs). We also analyzed (1) patient clinical features compared with a cohort of 44 patients who developed Ma2-PNS without receiving ICI treatment and (2) the frequency of neuronal antibody detection before and after ICI implementation. METHODS: Retrospective nationwide study of all patients with Ma2-PNS developed during ICI treatment between 2017 and 2018. RESULTS: Our series of patients included 5 men and 1 woman (median age, 63 years). The patients were receiving nivolumab (n = 3), pembrolizumab (n = 2), or a combination of nivolumab and ipilimumab (n = 1) for treatment of neoplasms that included lung (n = 4) and kidney (n = 1) cancers and pleural mesothelioma (n = 1). Clinical syndromes comprised a combination of limbic encephalitis and diencephalitis (n = 3), isolated limbic encephalitis (n = 2), and a syndrome characterized by ophthalmoplegia and head drop (n = 1). No significant clinical difference was observed between our 6 patients and the overall cohort of Ma2-PNS cases. Post-ICI Ma2-PNS accounted for 35% of the total 17 Ma2-PNS diagnosed in our center over the 2017-2018 biennium. Eight cases had been detected in the preceding biennium 2015-2016, corresponding to a 112% increase of Ma2-PNS frequency since the implementation of ICIs in France. Despite ICI withdrawal and immunotherapy, 4/6 patients died, and the remaining 2 showed a moderate to severe disability. CONCLUSIONS: We show a clear association between ICI use and increased diagnosis of Ma2-PNS. Physicians need to be aware that ICIs can trigger Ma2-PNS because clinical presentation can be challenging.

Worsening and newly diagnosed paraneoplastic syndromes following anti-PD-1 or anti-PD-L1 immunotherapies, a descriptive study.

BACKGROUND: Paraneoplastic syndromes (PNS) are autoimmune disorders specifically associated with cancer. There are few data on anti-PD-1 or anti-PD-L1 immunotherapy in patients with a PNS. Our objective was to describe the outcome for patients with a pre-existing or newly diagnosed PNS following the initiation of anti-PD-1 or anti-PD-L1 immunotherapy. METHODS: We included all adult patients (aged ≥18) treated with anti-PD-1 or anti-PD-L1 immunotherapy for a solid tumor, diagnosed with a PNS, and registered in French pharmacovigilance databases. Patients were allocated to cohorts 1 and 2 if the PNS had been diagnosed before vs. after the initiation of immunotherapy, respectively. FINDINGS: Of the 1304 adult patients screened between June 27th, 2014, and January 2nd, 2019, 32 (2.45%) had a PNS and were allocated to either cohort 1 (n = 16) or cohort 2 (n = 16). The median (range) age was 64 (45-88). The tumor types were non-small-cell lung cancer (n = 15, 47%), melanoma (n = 6, 19%), renal carcinoma (n = 3, 9%), and other malignancies (n = 8, 25%). Eleven (34%) patients presented with a neurologic PNS, nine (28%) had a rheumatologic PNS, eight (25%) had a connective tissue PNS, and four (13%) had other types of PNS. The highest severity grade for the PNS was 1-2 in 10 patients (31%) and ≥ 3 in 22 patients (69%). Four patients (13%) died as a result of the progression of a neurologic PNS (encephalitis in three cases, and Lambert-Eaton syndrome in one case). Following the initiation of immunotherapy, the PNS symptoms worsened in eight (50%) of the 16 patients in cohort 1. INTERPRETATION: Our results show that PNSs tend to be worsened or revealed by anti-PD-1 or anti-PD-L1 immunotherapy. Cases of paraneoplastic encephalitis are of notable concern, in view of their severity. When initiating immunotherapy, physicians should carefully monitor patients with a pre-existing PNS.

UV-mediated hydrophosphinylation of unactivated alkenes with phosphinates under batch and flow conditions.

A UV-mediated hydrophosphinylation of unactivated alkenes with H-phosphinates and hypophosphorous acid under radical free conditions is presented. The reaction affords selectively a large number of structurally diverse organophosphorous compounds in moderate to good yields under mild reaction conditions in the presence of an organic sensitizer as catalyst irradiated by UV-A LEDs. Furthermore, the high yielding hydrophosphinylation in continuous flow is disclosed.

Assessment of Per-Endoscopic Placement of Fiducial Gold Markers for Small Peripheral Lung Nodules < 20 mm Before Stereotactic Radiation Therapy.

BACKGROUND: Stereotactic radiotherapy is used to treat peripheral lung cancer in inoperable patients. Placement of fiducial gold markers (FMs) is crucial for tracking small lesions that are not visible on chest radiographs. Our objective was to assess endoscopic FM placement in small peripheral lung nodules (PLNs) that are not trackable using automated tracking software. METHODS: All patients benefiting from virtual bronchoscopy and radial endobronchial ultrasonography (R-EBUS)-guided placement of FMs for PLNs < 20 mm were included. After confirmation by biopsy sampling, a gold-seed FM was inserted into the nodule using a bronchial brush, without the use of fluoroscopy. The performance and complications of the procedure were recorded. RESULTS: From May 2010 to June 2015, FMs were placed in the PLNs of 54 consecutive patients, 34 of whom presented with a nodule < 20 mm. Seventy-six percent of the procedures were performed using local anesthesia on an outpatient basis. The median long- and short-axis diameters of nodules were 15 mm (9-20 mm) and 11 mm (6-20 mm), respectively, with 31 of 34 nodules exhibiting a short axis of < 15 mm. In 23 cases (79%), histologic samples were obtained during the procedure that allowed FM placement. Migration occurred in six cases, including two in the hours following the procedure. FMs were in place and visible on CT imaging performed 3 months after radiation therapy in 80% of cases. No complications were reported. CONCLUSIONS: Diagnosis of peripheral nodules < 20 mm and FM placement using R-EBUS are efficient and safe in a single procedure.

Addressing nonlinearities in Monte Carlo.

Monte Carlo is famous for accepting model extensions and model refinements up to infinite dimension. However, this powerful incremental design is based on a premise which has severely limited its application so far: a state-variable can only be recursively defined as a function of underlying state-variables if this function is linear. Here we show that this premise can be alleviated by projecting nonlinearities onto a polynomial basis and increasing the configuration space dimension. Considering phytoplankton growth in light-limited environments, radiative transfer in planetary atmospheres, electromagnetic scattering by particles, and concentrated solar power plant production, we prove the real-world usability of this advance in four test cases which were previously regarded as impracticable using Monte Carlo approaches. We also illustrate an outstanding feature of our method when applied to acute problems with interacting particles: handling rare events is now straightforward. Overall, our extension preserves the features that made the method popular: addressing nonlinearities does not compromise on model refinement or system complexity, and convergence rates remain independent of dimension.

Monte carlo estimates of domain-deformation sensitivities.

It is shown that, when a Monte Carlo algorithm is used for estimation of any physical quantity A, a simple and fast additional procedure can be implemented that simultaneously estimates the sensitivity of A to any problem parameter. The proposed approach is general and systematic in the sense that: (i) it includes domain-deformation sensitivities, i.e., cases where a change in the parameter modifies the domain over which the sampled random variables are defined and (ii) a simple generic procedure is presented to address all remaining free choices in terms of variance minimization.